Evolution by Natural Selection is a Self ish Process

1. Evolution by Natural Selection is a Selfish Process Things (units) that survive & reproduce relatively more of self become relatively more common over time. An important way to increase survival & reproduction is to form cooperative coalitions. In evolutionary theory, the main mechanisms that underpin cooperation (by stabilizing against cheating) are reciprocity and kin selection. By helping kin, a ‘unit’ helps reproduce copies of shared genes (replicators). In diploid sexual species, full siblings share 1/2 of their genes by common descent. All the cells within a body (vehicle) that descend from a fertilized egg are a clone and share all genes (except for mutations, ex cancers) & kinship = 1; this makes for a very cooperative coalition - a body. Most cells in a clonal body don’t reproduce across generations; they increase copies of shared genes in their ‘close kin’ - the gametes. It is the job of the immune system to stabilize this big cooperative coalition of cells by making sure everyone is on the same team - the ‘self team.’

2. Cells of the Immune System Lymphoid stem cells develop into lymphocytes. … two major classes are B cells and T cells. Myeloid stem cells develop into granule-containing inflammatory cells: Basophils – release histamines, prostaglandins Chemokines, pyrogens, etc. Eosinophils & Natural Killer cells– ‘bombs’ Other Myeloid stem cells develop into phagocytes … neutrophils – fast & brief Monocytes become big persistent macrophages Fig 43.1: An overview of defenses (antigen-independent)

3. Mucus is also rich in phagocytes and IgA antibodies Mucus traps microbes and other particles that contact it. In the trachea, ciliated epithelial cells sweep out mucus with its trapped microbes, preventing them from entering the lungs. (antigen-independent) Beyond their role as a physical barrier, the skin & mucous membranes counter pathogens with chemical defenses. In humans, for example, secretions from sebaceous and sweat glands give the skin a pH ranging from 3 to 5; acidic enough to prevent colonization by many microbes. (Normal skin bacteria are adapted to acidic, relatively dry env.) Microbial colonization is also inhibited by the washing action of saliva, tears, and mucous secretions. These secretions contain antimicrobial proteins, like the enzyme lysozyme, which digests peptidoglycan (fig 27.5) in the cell walls of many bacteria. Most microbes in food or water or swallowed mucus are destroyed by the highly acidic environment of the stomach. However, Hepatitis A virus is one of many pathogens that survives gastric acidity and enters to the body via the digestive tract.

4. (antigen-independent) http://www.cat.cc.md.us/courses/bio141/lecguide/unit1/bacpath/cytogn.html#neut Lipopolysaccharide LPS (aka endotoxin) from the gram-negative bacterial cell wall binds to LPS receptors on monocytes, macrophages and neutrophils. The binding of LPS to the LPS (CD14) receptor and Il-8 to Il-8 receptors on neutrophils stimulates them to release proteases and toxic oxygen radicals for extracellular killing. Microbes that penetrate the first line of defense, face the internal nonspecific defense: phagocytosis, ingestion by certain types of white cells. Phagocytic neutrophils constitute 60-70% of all leukocytes. Damaged cells release chemical signals that attract neutrophils {proinflammatory cytokines like interleukin-8 (Il-8) – aka chemokines}. The neutrophils enter the infected tissue, engulfing and destroying microbes. All components of the non-specific immune system are modulated byproducts of the specific immune system, such as interleukins, interferon-gamma, antibody, etc

5. (antigen-independent) Fig 43.3  Phagocytosis: This micrograph shows fibril-like pseudopodia of a macrophage attaching to rod-shaped bacteria, which will be ingested and destroyed. A macrophage engulfs a microbe in a vacuole that fuses with a lysosome (Fig 7.14). The lysosome has two ways of killing the trapped microbe: 1) w/ toxic forms of oxygen like superoxide anion and nitric oxide, 2) w/ lysosomal enzymes, including lysozyme. Phagocytic Monocytes (5% of leukocytes) circulate in the blood for only a few hours, then migrate into tissues, developing into large macrophages ("big eaters") = Macrophages, the largest phagocytic cells. Some microbes have evolved mechanisms for evading phagocytic destruction. Some bacteria have outer capsules to which a macrophage cannot attach. Others, like Mycobacterium tuberculosis, are readily engulfed {it binds to macrophage surface receptors for the sugar mannose} but are resistant to lysosomal destruction {it can inhibit phagosome-lysosome fusion; the exact mechanism is not known} and can even reproduce inside a macrophage.

6. (antigen-independent) Nonspecific defense also includes natural killer (NK) cells. NK cells do not attack microorganisms directly; instead, they destroy virus-infected body cells (as well as abnormal & cancerous cells). NK cells are not phagocytic; rather, they mount an attack on the cell's membrane, causing the cell to lyse (burst open). www.bio.ic.ac.uk/ research/dmd/ NK cells require the order of a minute or two to survey a target cell. A lack of such accumulation of MHC I protein (HLA-C) signifies to the Natural Killer cell that something is abnormal in the cell, e.g. it is virally infected, and it should be killed. About 1.5% of all leukocytes are eosinophils. Their main contribution is against larger parasitic invaders, such as the blood fluke Schistosoma mansoni. Eosinophils position themselves against the external wall of a parasite and discharge destructive enzymes from cytoplasmic granules. These cells have only limited phagocytic activity. Phagocyte function is intimately associated with an effective inflammatory response and also with certain antimicrobial proteins.

7. Cellular Mediators of Inflammation -http://web.indstate.edu/nurs/mary/PATHOPHY.htm Neutrophils and Monocytes are drawn by the chemotactic chemicals, Neutrophils are highly phagocytic leukocytes … contain lysosomal granules (enzymes) which digest substances that they engulf. Monocytesare large immature forms of a macrophage … Chemical Mediators of Inflammation -http://web.indstate.edu/nurs/mary/PATHOPHY.htm Histamine: In response to injury, granulated leukocytes known as mast cells (fixed in the body organs) and basophils (flowing in blood stream) release histamine which causes dilation of local blood vessels … bronchial constriction (smooth muscle) and mucus production, {antihistamines fill receptor cell ‘locks’ w/o turning the key - preempt histamine keys;} Bradykinin:… which causes increases heart rate & vascular permeability … The kinins are also responsible for pain. Prostaglandins: … attractneutrophils, increase platelet aggregation to help clotting. cause redness (increase vasodilation and permeability) pain (increase sensitivity of nerve endings)

8. Certain bacterial infections can induce an an overwhelming systemic inflammatory response known as septic shock . Characterized by high fever and low blood pressure, septic shock is the most common cause of death in U.S. critical care units. Leukocytes also release molecules called pyrogens, which set the body's thermostat at a higher temperature – fever: phagocytized bits of bacterial pyrogens (cell wall etc) increase the production of interleukin-1 in phagocytes. IL-1 (endogenous pyrogen or leukocyte pyrogen) increases the local production of prostaglandins in the anterior hypothalamus, increasing the temperature set-point. Fever can be reduced by aspirin which inhibits the cyclooxygenase enzyme necessary for the synthesis of prostaglandins.

9. http://www.mnwelldir.org/docs/immune/immune1.htm There are many types of interferons, and their name derives from their function: the ability to interfere with viral infections. When a cell is attacked by a virus, though it cannot save itself, it can create an interferon that will warn other cells of an impending infection. Having been warned, the uninfected cells arm themselves with antiviral substances that keep the virus from replicating (reproducing themselves) in the uninfected cells. {the actual mechanisms are complex & not well known, see http://www.bio.indiana.edu/studies/ugrad/M430/INTERFERON.html } Some interferons act as chemokines, attracting & activating phagocytes. Interferons are not virus specific. The complement system - later.

10. This strain has a gene that interferes w/ interferon! & prevents infected cells from signaling for immune response. Lethal H5N1 influenza viruses escape host anti-viral cytokine responsesSeo SH, Hoffmann E, Webster RG NATURE MEDICINE 8 (9): 950-954 SEP 2002

11. http://www.thebody.com/step/immune.html The Organs of the Immune System Bone Marrow -- All the cells of the immune system are initially derived from the bone marrow … bone marrow-derived stem cells differentiate into … B cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets. Immature thymocytes … leave the bone marrow and migrate into the thymus. Thymus -- The function of the thymus is to produce mature T cells. Through a maturation process sometimes referred to as thymic education, T cells that are beneficial to the immune system are spared, while T cells that evoke a detrimental autoimmune response are eliminated. The mature T cells are then released into the bloodstream. In immature lymphocytes, genes for immunoglobulins mutate like crazy, creating zillions of mutant ‘locks,’ each w/ a different key to its ignition. Most of these mutant immunoglobulins are ‘ignited’ by self-antigens (95%). Self-tolerance results from clonal deletion: maturing lymphocytes that react intensely in Bone or Thymus are convinced to commit suicide (apoptosis, Fig 21.18)

13. The TH helper subset, also called CD4+ T cell coordinates immune regulation. The main function of the TH helper cell is to augment immune responses by the secretion of {chemokines - interleukins} that activate other white blood cells. http://www.thebody.com/step/immune.html Cells of the Immune System T-Cells are divided into two major subsets.

14. T cells interact with cell surface glycoproteins encoded by a family of genes called the major histocompatibility complex (MHC). In humans, MHC glycoproteins are known as HLA (Human Leukocyte Antigens). Through a process known as antigen presentation, an MHC molecule cradles a 9 amino acid fragment of an intracellular protein antigen in its groove, carries it to the cell surface, and "presents" it to an antigen receptor on a T cell. {see Falk et al 2002. Nature 348,248-251} (a) Class I MHC molecules found on almost all nucleated cells in the body present to Cytotoxic T cells (TC), which then kill the presenter. (b) Class II MHC molecules are made by only a few cell types, chiefly macrophages and B cells (called antigen-presenting cells (APCs)) that ingest bacteria (and viruses) and then destroy them. Class II MHC molecules in these cells collect peptide remnants of this degradation and present them to helper T cells, which send out chemical signals that incite other cell types to fight the pathogen

15. …each female student was asked to rate the odours of six T-shirts. Oooohh - he smells so … different! They scored male body odours as more pleasant when they differed from the men in their MHC {II} than when they were more similar. MHC-dependent mate preferences in humans. Wedekind et al. 1995. Proc. Roy. Soc. Lond. B 260: 245-249.

16. The cytotoxic TC killer subset or CD8+ T cell. … directly kill certain tumor cells, viral-infected cells and sometimes parasites. perforin, a protein that forms pores in the target cell's membrane. http://www.thebody.com/step/immune.html Cells of the Immune System

17. http://www.thebody.com/step/immune.html Cells of the Immune System B Cells -- The major function of B lymphocytes is the production of antibodies in response to foreign proteins of bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to one particular protein. Antibody … binding to a foreign substance or antigen, often is critical as a means of signaling other cells to engulf, kill or remove that substance from the body.

18. Each antibody is made up of two identical heavy chains and two identical light chains, shaped to form a Y. … the tips of the Y's arms = the variable region = the antigen-binding site … allow the antibody to recognize a matching antigen, much as a lock matches a key. The stem of the Y links the antibody to other participants in the immune defenses. This area is identical in all antibodies of the same class … http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Antibodies {& membrane-bound receptors}

19. The answer is that antibody genes are pieced together from widely scattered bits of DNA, and the possible combinations are nearly endless. As this gene forms, it assembles segments that will determine the variable-V, joining-J, and constant-C segments of this antibody molecule … http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Antibody Genes Scientists long wondered how all the genetic information needed to make millions of different antibodies could fit in a limited number of genes.

20. IgG, the major immunoglobulin in the blood, is also able to enter tissue spaces; it works efficiently to coat microorganisms, IgD is inserted into the membrane of B cells, where it somehow regulates the cell's activation. IgE is normally present in only trace amounts, but it is responsible for the symptoms of allergy {it triggers mast cells in mucous membranes to release histamines}. IgA—a doublet— concentrates in body fluids such as tears, saliva, and the secretions of the respiratory and gastrointestinal tracts{snot}. It is, thus, in a position to guard the entrances to the body. IgM usually combines in star-shaped clusters. It tends to remain in the bloodstream, where it is very effective in killing bacteria. http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Antibodies belong to a family of large protein molecules known as immunoglobulins.

22. http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Complement proteins circulate in the blood in an inactive form. The so-called "complement cascade" is set off when the first complement molecule, C1, encounters antibody bound to antigen in an antigen-antibody complex. The end product is a cylinder that punctures the cell membrane and, by allowing fluids and molecules to flow in and out, dooms the target cell. Complement The complement system consists of a series of proteins that "complement" the work of antibodies in destroying bacteria.

23. Immunity: Short- and Long-Term Cell Memory Whenever T cells and B cells are activated, some become "memory" cells. The next time that an individual encounters that same antigen, the immune system is primed to destroy it quickly. Short-term immunity can be transferred passively via antibody-containing serum; similarly, infants are protected by antibodies they receive from their mothers (IgG antibodies cross the placenta, IgA antibodies are passed in breast milk). http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Long-term immunity can be stimulated not only by infection but also by vaccines made from infectious agents that have been inactivated or, more commonly, from minute portions of the microbe. Note the use of passive immunity w/ IgG to Rh factor at 1st birth preempt Rh- mom from developing active memory & strong attack on 2nd child.

24. The first time an allergy-prone person is exposed to an allergen—for instance, grass pollen— the individual's B cells make large amounts of grass pollen IgE antibody. These IgE molecules attach to granule-containing cells known as mast cells, which are plentiful in the lungs, skin, tongue, and linings of the nose and gastrointestinal tract. http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Disorders of the Immune System: Allergy Allergies such as hay fever and hives are related to the antibody known as IgE. The next time that person encounters grass pollen, the IgE-primed mast cell releases{histamines}that cause the wheezing, sneezing, and other symptoms of allergy. To Desensitize the person to the antigen - (allergy shots) Give repeated small doses of the antigen intramuscularly. This leads to a build up of IgG, {circulating in blood & lymph} which clears out the antigen before it gets to the IgE on the Mast cells. Not 100% effective, but it does help some.

25. … type I or juvenile-onset diabetes is due to the combined attack of T cells and antibodies directed against the ß cells of the pancreas that normally produce insulin People w/ systemic lupus erythematosus … have developed an immune response to their own DNA, and the presence of anti-DNA antibodies in their serum is one mechanism of diagnosis lupus … Rheumatoid Arthritis: Some people produce the rheumatoid factor which is an IgM autoantibody. This auto IgM binds to the Fc part of IgG, forming immune complexes, which lodge in the joints and cause inflammation of the joint. {see Vinuesa & Goodnow 2002. Nature 416,595-598} http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm Disorders of the Immune System: Autoimmune Disease {See: http://www.montana.edu/wwwwami/523/Reading11.htm} Sometimes the immune system's recognition apparatus breaks down, and the body begins to manufacture antibodies and T cells directed against the body's own cells and organs.

26. is an immunodeficiency disorder caused by {HIV}, a virus that destroys helper T cells. CD4 molecules on helper T cells enhance the binding w/ class II MHC-bearing antigen-presenting cells. HIV binds to CD4 & helper T cells are highly susceptible to infection. The AIDS virus splices its DNA into the DNA of the cell it infects; the cell is thereafter directed to churn out new viruses. Disorders of the Immune System: AIDS

27. Immunity and Cancer When normal cells turn into cancer cells, some of the antigens on their surface change. These altered antigens flag immune defenders, including cytotoxic T cells, natural killer cells, & macrophages. Social stress in laboratory rats - Behavior, immune function, and tumor metastasis.Stefanski V. PHYSIOLOGY & BEHAVIOR 73 (3): 385-391 JUN 2001Abstract:… in subdominant males after 2 days of continuous social confrontation … elevated plasma concentrations of adrenal hormones … lower numbers of blood CD4 and CD8 T cells as well as reduced activity levels of T cells and natural killer (NK) cells … A 10-fold lower tumor clearance in subdominant males demonstrates suppression of the animals' capacity to prevent metastatic development. … http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm According to one theory, patrolling cells of the immune system provide continuing bodywide surveillance, spying out and eliminating cells that undergo malignant transformation. Tumors develop when the surveillance system breaks down or is overwhelmed {or when the immune system is suppressed, ex by stress}

28. Abstract:Background: Increased frequency and severity of herpesvirus infections are common in individuals with impaired cellular immunity … This study investigated immune responses and latent herpesvirus reactivation during a 9-d spaceflight. … Conclusions: … spaceflight and associated stresses reactivate latent herpesviruses … acute changes in neuroendocrine hormones mediate these changes in part by downregulating cellular immunity. … { Think Happy Thoughts – ‘humoral immunity’! } Immune responses and latent herpesvirus reactivation in spaceflight. Stowe et al. Aviation Space and Environmental Medicine 72 (10): 884-891 OCT 2001. http://rex.nci.nih.gov/behindthenews/uis/07uis/uis07.htm The Immune System and the Nervous System Biological links between the immune system and the nervous system exist at several levels.